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Neuroscience Bulletin 2024年第1期40卷 35-49页

作者： Shuhui Dai Yuan Feng Chuanhao Lu Hongchen Zhang Wenke Ma Wenyu Xie Xiuquan Wu Peng Luo Lei Zhang Fei Fei Zhou Fei Xia Li Department of Neurosurgery Xijing HospitalFourth Military Medical UniversityXi'an 710000China National Translational Science Center for Molecular Medicine and Department of Cell Biology Fourth Military Medical UniversityXi'an 710000China Department of Neurosurgery The Central Hospital of BaojiBaoji 721000China Department of Ophthalmology Xijing HospitalFourth Military Medical UniversityXi'an 710000China

Acute hypobaric hypoxic brain damage is a potentially fatal high-altitude sickness.Autophagy plays a critical role in ischemic brain injury,but its role in hypo-baric hypoxia(HH)remains unknown.Here we used an HH chamber to demonstrate that acute HH exposure impairs autophagic activity in both the early and late stages of the mouse brain,and is partially responsible for HH-induced oxidative stress,neuronal loss,and brain damage.The autophagic agonist rapamycin only promotes the initiation of autophagy.By proteome analysis,a screen showed that protein dynamin2(DNM2)potentially regulates autophagic flux.Overexpression of DNM2 significantly increased the formation of autolysosomes,thus maintaining autophagic flux in combination with rapamycin.Furthermore,the enhancement of autophagic activity attenuated oxidative stress and neurological deficits after HH exposure.These results contribute to evidence supporting the conclusion that DNM2-mediated autophagic flux represents a new therapeutic target in HH-induced brain damage.

关键词： Autophagy-Proteomics Oxidative stress Hypobaric hypoxia-Brain injury

Homer1a reduces inflammatory response after retinal ischemia/reperfusion injury

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Neural Regeneration Research 2024年第7期19卷 1608-1617页

作者： Yanan Dou Xiaowei Fei Xin He Yu Huan Jialiang Wei Xiuquan Wu Weihao Lyu Zhou Fei Xia Li Fei Fei Department of Neurosurgery Xijing HospitalAir Force Military Medical UniversityXi’anShaanxi ProvinceChina Department of Ophthalmology Xijing HospitalAir Force Military Medical UniversityXi’anShaanxi ProvinceChina

Elevated intraocular pressure(IOP)is one of the causes of retinal ischemia/reperfusion injury,which results in NRP3 inflammasome activation and leads to visual damage.Homerla is repo rted to play a protective role in neuroinflammation in the cerebrum.However,the effects of Homerla on NLRP3inflammasomes in retinal ischemia/reperfusion injury caused by elevated IOP remain unknown.In our study,animal models we re constructed using C57BL/6J and Homer1^(flox/-)/Homerla^(+/-)/Nestin-Cre^(+/-)mice with elevated IOP-induced retinal ischemia/repe rfusion injury.For in vitro expe riments,the oxygen-glucose deprivation/repe rfusion injury model was constructed with M uller cells.We found that Homerla ove rexpression amelio rated the decreases in retinal thickness and Muller cell viability after ischemia/reperfusion injury.Furthermore,Homerla knockdown promoted NF-κB P65^(Ser536)activation via caspase-8,NF-κB P65 nuclear translocation,NLRP3 inflammasome formation,and the production and processing of interleukin-1βand inte rleukin-18.The opposite results we re observed with Homerla ove rexpression.Finally,the combined administration of Homerla protein and JSH-23 significantly inhibited the reduction in retinal thickness in Homer1^(flox/-)Homer1a^(+/-)/Nestin-Cre^(+/-)mice and apoptosis in M uller cells after ischemia/reperfusion injury.Taken together,these studies demonstrate that Homer1a exerts protective effects on retinal tissue and M uller cells via the caspase-8/NF-KB P65/NLRP3 pathway after I/R injury.

关键词： caspase-8 Homer1a interleukin-18 interleukin-1β intraocular pressure ischemia/reperfusion injury JSH-23 Müller cells NLRP3 nuclear factor-kB p65 retina

Lactate:a prospective target for therapeutic intervention in psychiatric disease

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Neural Regeneration Research 2024年第7期19卷 1473-1479页

作者： Yanhui Cai Haiyun Guo Tianle Han Huaning Wang Department of Psychiatry Xijing HospitalFourth Military Medical UniversityXi’anShaanxi ProvinceChina Department of Anesthesiology and Perioperative Medicine Xijing HospitalFourth Military Medical UniversityXi’anShaanxi ProvinceChina

Although antipsychotics that act via monoaminergic neurotransmitter modulation have considera ble therapeutic effect,they cannot completely relieve clinical symptoms in patients suffering from psychiatric disorde rs.This may be attributed to the limited range of neurotransmitters that are regulated by psychotropic drugs.Recent findings indicate the need for investigation of psychotropic medications that target less-studied neurotransmitte rs.Among these candidate neurotransmitters,lactate is developing from being a waste metabolite to a glial-neuronal signaling molecule in recent years.Previous studies have suggested that cerebral lactate levels change considerably in numerous psychiatric illnesses;animal experiments have also shown that the supply of exogenous la ctate exerts an antidepressant effect.In this review,we have described how medications targeting newer neurotransmitte rs offer promise in psychiatric diseases;we have also summarized the advances in the use of lactate(and its corresponding signaling pathways)as a signaling molecule.In addition,we have described the alterations in brain lactate levels in depression,anxiety,bipolar disorder,and schizophrenia and have indicated the challenges that need to be overcome before brain lactate can be used as a therapeutic target in psychopharmacology.

关键词： antidepressant anxiety bipolar disorder depression lactate psychiatric disease psychopharmacology schizophrenia signal molecular therapeutics

Hydralazine represses Fpn ubiquitination to rescue injured neurons via competitive binding to UBA52

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Journal of Pharmaceutical Analysis 2024年第1期14卷 86-99页

作者： Shengyou Li Xue Gao Yi Zheng Yujie Yang Jianbo Gao Dan Geng Lingli Guo Teng Ma Yiming Hao Bin Wei Liangliang Huang Yitao Wei Bing Xia Zhuojing Luo Jinghui Huang Department of Orthopedics Xijing HospitalFourth Military Medical UniversityXi'an710032China

A major impedance to neuronal regeneration after peripheral nerve injury (PNI) is the activation of various programmed cell death mechanisms in the dorsal root ganglion. Ferroptosis is a form of programmed cell death distinguished by imbalance in iron and thiol metabolism, leading to lethal lipid peroxidation. However, the molecular mechanisms of ferroptosis in the context of PNI and nerve regeneration remain unclear. Ferroportin (Fpn), the only known mammalian nonheme iron export protein, plays a pivotal part in inhibiting ferroptosis by maintaining intracellular iron homeostasis. Here, we explored in vitro and in vivo the involvement of Fpn in neuronal ferroptosis. We first delineated that reactive oxygen species at the injury site induces neuronal ferroptosis by increasing intracellular iron via accelerated UBA52-driven ubiquitination and degradation of Fpn, and stimulation of lipid peroxidation. Early administration of the potent arterial vasodilator, hydralazine (HYD), decreases the ubiquitination of Fpn after PNI by binding to UBA52, leading to suppression of neuronal cell death and significant acceleration of axon regeneration and motor function recovery. HYD targeting of ferroptosis is a promising strategy for clinical management of PNI.

关键词： Ferroptosis UBA52 Ferroportin Ubiquitination Hydralazine Peripheral nerve injury

Translocation of telomerase reverse transcriptase coincided with ATP release in postnatal cochlear supporting cells

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Neural Regeneration Research 2024年第5期19卷 1119-1125页

作者： Yukai Zhang Keyong Tian Wei Wei Wenjuan Mi Fei Lu Zhenzhen Liu Qingwen Zhu Xinyu Zhang Panling Geng Jianhua Qiu Yongli Song Dingjun Zha Department of Otolaryngology Xijing HospitalFourth Military Medical UniversityXi’anShaanxi ProvinceChina

The spontaneous bursts of electrical activity in the developing auditory system are derived from the periodic release of adenosine triphosphate(ATP)by supporting cells in the Kölliker’s organ.However,the mechanisms responsible for initiating spontaneous ATP release have not been determined.Our previous study revealed that telomerase reverse transcriptase(TERT)is expressed in the basilar membrane during the first postnatal week.Its role in cochlear development remains unclear.In this study,we investigated the expression and role of TERT in postnatal cochlea supporting cells.Our results revealed that in postnatal cochlear Kölliker’s organ supporting cells,TERT shifts from the nucleus into the cytoplasm over time.We found that the TERT translocation tendency in postnatal cochlear supporting cells in vitro coincided with that observed in vivo.Further analysis showed that TERT in the cytoplasm was mainly located in mitochondria in the absence of oxidative stress or apoptosis,suggesting that TERT in mitochondria plays roles other than antioxidant or anti-apoptotic functions.We observed increased ATP synthesis,release and activation of purine signaling systems in supporting cells during the first 10 postnatal days.The phenomenon that TERT translocation coincided with changes in ATP synthesis,release and activation of the purine signaling system in postnatal cochlear supporting cells suggested that TERT may be involved in regulating ATP release and activation of the purine signaling system.Our study provides a new research direction for exploring the spontaneous electrical activity of the cochlea during the early postnatal period.

关键词： apoptosis ATP release Ca2+transients cochlea mitochondrial function reactive oxygen species spontaneous electrical activity supporting cells

SENP3 Promotes Mantle Cell Lymphoma Development through Regulating Wnt10a Expression

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Current Medical Science 2024年第1期44卷 134-143页

作者： Yan-ni MA Yun-ding ZOU Zhi-long LIU Gui-xian WU Yuan-ze ZHOU Cheng-xin LUO Xiang-tao HUANG Ming-ling XIE Shuang-nian XU Xi LI Department of Hematology Southwest HospitalThird Military Medical University(Army Medical University)Chongqing 400038China Department of Hematology the Third Affiliated Hospital(Daping Hospital)Third Military Medical University(Army Medical University)Chongqing 400042China

Objective SUMO-specific protease 3(SENP3),a member of the SUMO-specific protease family,reverses the SUMOylation of SUMO-2/3 conjugates.Dysregulation of SENP3 has been proven to be involved in the development of various tumors.However,its role in mantle cell lymphoma(MCL),a highly aggressive lymphoma,remains unclear.This study was aimed to elucidate the effect of SENP3 in MCL.Methods The expression of SENP3 in MCL cells and tissue samples was detected by RT-qPCR,Western blotting or immunohistochemistry.MCL cells with stable SENP3 knockdown were constructed using short hairpin RNAs.Cell proliferation was assessed by CCK-8 assay,and cell apoptosis was determined by flow cytometry.mRNA sequencing(mRNA-seq)was used to investigate the underlying mechanism of SENP3 knockdown on MCL development.A xenograft nude mouse model was established to evaluate the effect of SENP3 on MCL growth in vivo.Results SENP3 was upregulated in MCL patient samples and cells.Knockdown of SENP3 in MCL cells inhibited cell proliferation and promoted cell apoptosis.Meanwhile,the canonical Wnt signaling pathway and the expression of Wnt10a were suppressed after SENP3 knockdown.Furthermore,the growth of MCL cells in vivo was significantly inhibited after SENP3 knockdown in a xenograft nude mouse model.Conclusion SENP3 participants in the development of MCL and may serve as a therapeutic target for MCL.

关键词： mantle cell lymphoma SENP3 cell proliferation apoptosis

Photobiomodulation inhibits the expression of chondroitin sulfate proteoglycans after spinal cord injury via the Sox9 pathway

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Neural Regeneration Research 2024年第1期19卷 180-189页

作者： Zhihao Zhang Zhiwen Song Liang Luo Zhijie Zhu Xiaoshuang Zuo Cheng Ju Xuankang Wang Yangguang Ma Tingyu Wu Zhou Yao Jie Zhou Beiyu Chen Tan Ding Zhe Wang Xueyu Hu Department of Orthopedics Xijing HospitalFourth Military Medical UniversityXi’anShaanxi ProvinceChina

Both glial cells and glia scar greatly affect the development of spinal cord injury and have become hot spots in research on spinal cord injury treatment.The cellular deposition of dense extracellular matrix proteins such as chondroitin sulfate proteoglycans inside and around the glial scar is known to affect axonal growth and be a major obstacle to autogenous repair.These proteins are thus candidate targets for spinal cord injury therapy.Our previous studies demonstrated that 810 nm photo biomodulation inhibited the formation of chondroitin sulfate proteoglycans after spinal cord injury and greatly improved motor function in model animals.However,the specific mechanism and potential targets involved remain to be clarified.In this study,to investigate the therapeutic effect of photo biomodulation,we established a mouse model of spinal cord injury by T9 clamping and irradiated the injury site at a power density of 50 mW/cm~2 for 50 minutes once a day for 7 consecutive days.We found that photobiomodulation greatly restored motor function in mice and down regulated chondroitin sulfate proteoglycan expression in the injured spinal cord.Bioinformatics analysis revealed that photobiomodulation inhibited the expression of proteoglycan-related genes induced by spinal cord injury,and versican,a type of proteoglycan,was one of the most markedly changed molecules.Immunofluorescence staining showed that after spinal cord injury,versican was present in astrocytes in spinal cord tissue.The expression of versican in primary astrocytes cultured in vitro increased after inflammation induction,whereas photobiomodulation inhibited the expression of ve rsican.Furthermore,we found that the increased levels of p-Smad3,p-P38 and p-Erk in inflammatory astrocytes were reduced after photobiomodulation treatment and after delivery of inhibitors including FR 180204,(E)-SIS3,and SB 202190.This suggests that Sma d 3/Sox9 and MAP K/Sox9 pathways may be involved in the effects of photobiomodulation.In summary,our findings show that photobiomodu

关键词： chondroitin sulfate proteoglycans Erk MAPK P38 photobiomodulation principal component analysis Smad3 Sox9 spinal cord injury versican

Subsequent strategies and underlying mechanism of acquired resistance to PD-1 axis inhibitors in advanced non-small cell lung cancer

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中华医学杂志(英文版) 2024年第7期137卷 880-882页

作者： Wang Huilan Cheng Xinyu Yang Fan Chen Lu Zhang Anmei Zhong Liangzhi Long Haixia Zhu Bo Wang Zhongyu Institute of Cancer Xinqiao hospital Third military Medical University Chongqing 400037 China

Circulating cell-free mtDNA as a new biomarker for cancer detection and management

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Cancer Biology & Medicine 2024年第2期21卷 105-110页

作者： Fan Peng Siyuan Wang Zehui Feng Kaixiang Zhou Huanqin Zhang Xu Guo Jinliang Xing Yang Liu State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Xijing hospital of Digestive Diseases Fourth Military Medical UniversityXi’an 710032China Department of Clinical Diagnosis Tangdu HospitalFourth Military Medical UniversityXi’an 710038China

Cancer is a major cause of death worldwide,and was responsible for 19.29 million new cases and 9.96 million deaths in 2020 alone.The total number of patients with cancer worldwide is estimated to reach 28 million by 2040.The American Association for Cancer Research has also estimated approximately 16.2 million cancer deaths by 20401.

关键词： Cancer cancer death

ZYX promotes invasion and metastasis of gastric cancer cells via WNK1/SNAI1axis

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Genes & Diseases 2024年第2期11卷 564-567页

作者： Yi Jiang Dongfang Xiang Xianmei Wen Mingmin He Yan Qin Xiaoxue Yao Zexuan Yan Xiuli Geng Yong Ren Xiongwei Cai Youhong Cui Yan Wang Institute of Pathology and Southwest Cancer Center Southwest HospitalArmy Medical University (Third Military Medical University)Chongqing 400038China Department of Pathology General Hospital of Central Theater Command of PLAWuhanHubei 430070China Department of Obstetrics and Gynecology Southwest HospitalArmy Medical University (Third Military Medical University)Chongqing 400038China Department of Pharmacy The Hospital of 83rd Group of PLAXinxiangHenan 453000China Department of Gynecology Chongqing Health Center for Women and ChildrenWomen and Children's Hospital of Chongqing Medical UniversityChongqing 400013China

Gastric cancer(GC)is the third most common cause of cancer death globally and a large portion of patients are diagnosed at advanced stages with cancer invasion and metastasis1,2.However,the mechanisms underlying the invasion and metastasis of GC remain to be delineated.ZYX plays critical roles in cell mobility via cytoskeleton regulation in various cell types.3 In this study,we further reported that ZYX promoted migration,invasion,and metastasis of GC cells.Mechanistically,ZYX promoted WNK1 activation and SNAl1 up-regulation,inducing epithelial-mesenchymal transition(EMT)to enhance the mobility of GC cells.Inhibition of WNK1 impaired the mobility of GC cells.Therefore,ZYX/WNK1 could be potential therapeutic targets for GC treatment.

关键词： WNK1 invasion metastasis